Received 11/28/2017 Review began 12/01/2017 Review ended 01/02/2018 Published 01/07/2018

© Copyright 2018Galkin et al. This is an open accessarticle distributed under the terms ofthe Creative Commons AttributionLicense CC-BY 3.0., which permitsunrestricted use, distribution, andreproduction in any medium,provided the original author andsource are credited.

Advanced Survival in Patients withMultiple Irradiations for Brain MelanomaMetastases and Associated Abscopal EffectMikhail V. Galkin , Andrey V. Golanov , Elena Vetlova , Sergey Banov, Valery V.Kostjuchenko

1. Department of Radotherapy and Radiosurgery, Federal State Autonomous Institution «n.n. BurdenkoNational Medical Research Center of Neurosurgery» of the Ministry of Health of the I Russian Federation2. Department of Radiation Oncology, Burdenko Neurosurgery Institute 3. Radiation OncologyDepartment, Burdenko Neurosurgical Institute 4. 5. Gamma Knife, Neurosurgery Business Center

Corresponding author: Mikhail V. Galkin, mgalkin@nsi.ru Disclosures can be found in Additional Information at the end of the article

AbstractBrain metastases are often detected in melanoma patients. Central nervous system (CNS)involvement is usually associated with poor prognosis. We describe a case of a female patientwith multiple melanoma brain metastases who survived for 49 months after detection of CNSinvolvement and the first radiosurgery. She underwent several courses of irradiation (fiveradiosurgeries, stereotactic hypofractionated radiotherapy, and whole brain radiotherapy),chemotherapy (started in 12 months after the first radiosurgery), and targeted therapy (started30 months after the first radiosurgery). The clear abscopal effect in the form of disappearanceof intradermal lesions was observed after the second radiosurgery without any systemictreatment. We believe that the application of combination of different treatment modalities cansignificantly prolong survival in certain patients with melanoma brain metastases, and can berecommended even in case of poor prognosis.

Categories: Radiation Oncology, Neurosurgery, OncologyKeywords: radiosurgery, abscopal effect, brain metastases, metastatic melanoma, hypofractionation

IntroductionMelanoma is characterized by high probability of brain involvement. From the stage of primarycutaneous melanoma, progression develops in about one-third of cases [1]. According toclinical and imaging data, central nervous system (CNS) metastases were found in 2-20% ofpatients and in 36-54% of cases according to autopsy studies [1]. The median overall survivalfor patients with melanoma brain metastases is 9.8 months [2]. Several treatments have beenshown to significantly improve the life expectancy in these patients. They are immunotherapyand targeted BRAF- and MEK-inhibitors [3, 4]. Data about the effectiveness of conventionalchemotherapy, whole brain radiotherapy, radiosurgery, and surgery are more controversial [3,5]. Much attention is paid to the investigation of the abscopal effect which is often observedafter a combination of immunotherapy with irradiation, and is associated with a higher survivalin patients with melanoma metastases [6]. The irradiation alone induces the effect very rarely.

We present a case of a female patient with melanoma who was treated with several courses ofirradiation (with five courses of radiosurgery (single fraction) among them, whole brainradiotherapy and stereotactic hypofractionated radiotherapy (three fractions)), which providedprolonged survival of 49 months from brain metastases detection. The interesting fact is that

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Open Access CaseReport DOI: 10.7759/cureus.2034

How to cite this articleGalkin M V, Golanov A V., Vetlova E, et al. (January 07, 2018) Advanced Survival in Patients with MultipleIrradiations for Brain Melanoma Metastases and Associated Abscopal Effect. Cureus 10(1): e2034. DOI10.7759/cureus.2034

the radiosurgical treatment was followed by the development of abscopal effect in the form ofdisappearance of intradermal lesions without any systemic therapy.

Case PresentationIn May 2011, a 37-year-old woman underwent surgical resection of the melanoma in the sacrumarea. Further investigation performed at the end of 2015 (when the analysis had becomeavailable) revealed malignant melanoma with V600M mutation in the BRAF gene. In May 2012,due to progression, the inguinal-femoral lymphadenectomy was performed. The patient wasnot recommended any systemic treatment. In June 2013, screening magnetic resonanceimaging (MRI) found multiple relatively small brain metastases without edema and mass effect.The Karnofsky performance status (KPS) was 90 at that time.

In the same month (25 months from the disease onset), the patient was treated with Gamma-Knife radiosurgery (Figure 1). During the session, overall 19 targets were irradiated with amarginal dose of 24 Gy prescribed for 52-91% isodose line. The mean volume of treatedmetastases composed 0.107 ccm (0.005-0.727 ccm). Despite the recommendation, the systemictreatment was postponed. Local oncologists evaluated her prognosis as very poor and refused toperform any systemic treatment. In six months, brain MRI demonstrated growth in four of 19previously irradiated metastases and emergence of five new lesions. At the same period, thepatient noticed the appearance of intradermal nodes on her arms and chest.

FIGURE 1: Demonstration of course of intracranial diseasewith serial magnetic resonance imaging (MRIs) (axial T1 withcontrast enhancement) from the first radiosurgery to targetedtherapy.Abbreviations on the left represent different stages of treatment: RS 1-5 – MRIs duringradiosurgeries, H – MRI before hypofractionated irradiation, TT – MRI before the initiation oftargeted therapy.

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The color of the contour indicates the stage when the lesion was treated: yellow – the 1stradiosurgery, orange – the 2nd radiosurgery, pink – the 3rd radiosurgery and hypofractionation,red – the 4th radiosurgery, blue – lesions before the initiation of targeted therapy.

Arrows point on posttreatment changes after the 3rd irradiation in the area of septa pellucida;asterisk indicates the hemorrhage which emerged in one of the lesion treated with the 4thradiosurgery.

The second course of radiosurgical irradiation of all new and recurring lesions was performedwith Gamma-Knife in January, 2014 (Figure 1). Nine lesions with the mean volume of 0.197 ccm(0.01-0.389 ccm) were irradiated with the marginal dose of 20 and 24 Gy prescribed to the 50-82% isodose line. The systemic treatment was not started. During three months afterradiosurgery, the patient noticed complete regression of intradermal metastases without anysystemic treatment. In six months, the new brain MRI showed dissemination of the diseasealong the ventricular system with the emergence of multiple small lesions, mainly, in thebodies of both lateral ventricles, and larger lesions in the hypothalamic area, pineal region andthe lateral parts of the fourth ventricle. No new metastases in the brain parenchyma wererevealed. The cerebrospinal fluid (CSF) cytology was not performed. At this moment (37 monthsafter the disease onset and 12 months after the first radiosurgery), the systemic treatment withCisplatin and Temozolomide was started.

In July 2014, the patient was treated with CyberKnife (Figure 1). The choice of the apparatuswas based on the shape of a conglomerate of metastases in the lateral ventricles and thedecision to perform hypofractionated irradiation. At the first stage, four metastases (in theposterior horn of the left lateral ventricle) with the total volume of 0.215 ccm were irradiatedradiosurgically with the mean dose of 20.3 Gy, and the prescription dose of 18.5 Gy for 77%isodose line. In two days, the second stage of hypofractionated treatment with CyberKnife waslaunched (Figure 2). The irradiation was performed in three fractions with 48 hoursinterfraction interval. The first target composed by 11 lesions (in the body of the left lateralventricle) with the total volume of 1.5 ccm, the second target composed by 11 lesions (in thebody of the right lateral ventricle) with the total volume of 3.2 ccm, and the third target (in thepineal region) with the volume of 0.4 ccm were irradiated up to mean dose of 24 Gy (22.6 Gyprescribed for 85% isodose line). Systemic treatment with Cisplatin and Temozolomide wascontinued up to 10 courses. MRI in two months after the irradiation revealed partial responseof several irradiated lesions, and stabilization of others. MRI in 12 months demonstratedcomplete response of the ventricular lesions. At the same time, the posttreatment changes inthe corpus callosum and septa pellucida were found. In 14 months, again, progression wasdetected, which manifested by the emergence of new metastases.

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FIGURE 2: Dose distribution during the hypofractionatedirradiation of ventricular lesions.Targets in the lateral ventricles are contoured with red and purple lines. Orange contour is theprescription isodose line.

Another radiosurgical treatment was performed with Gamma-Knife unit in September, 2015 (52months from the disease onset, 27 months from the first intracranial progression) (Figure 1).Sixteen targets with the mean volume 0.165 ccm (0.006-1.011 ccm) were irradiated with themarginal dose of 24 Gy prescribed to 51-92% isodose line. In two months, the patientexperienced rapid development of right-sided hemiparesis and aphasia. MRI demonstrated theemergence of 10 new metastases and hemorrhage in the place of metastasis in the left parietallobe. The BRAF mutation was found at this time, and targeted therapy (Vemurafenib) wasrecommended. Again, due to some problems, the recommended treatment was not started, andthe previous regimen with Cisplatin and Temozolomide was continued with grade 3-4treatment toxicity detected. In two months, MRI demonstrated more than 20 new metastasesand enlargement of 10 lesions found with previous MRI. Also, seven intradermal metastaseswere found in the skin of forearm, shoulder, and chest.

The targeted therapy with Dabrafenib and Trametinib was started in January, 2016 (30 monthsafter the first radiosurgery) (Figure 1). The treatment led to clinical and radiographicimprovement. During several months regression of aphasia and hemiparesis, improvement ofcognitive function and diminishing of intradermal lesions were detected. In four months, MRIrevealed partial regression of 10 metastases emerged after last radiosurgery. No new lesionswere detected. The posttreatment changes in corpus callosum and septa pellucida were stillvisible. In six months (11 months from the initiation of targeted therapy), the growth ofintradermal lesions was found. MRI showed the increase of size (of non-irradiated lesions) andquantity of metastases along with regression of posttreatment changes in corpus callosum and

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septa pellucida (Figure 3). The intensity of targeted therapy was increased. The next MRI (13months after targeted therapy initiation) revealed further enlargement of nine largest lesions(with MR characteristics different from other lesions) with minor growth of other metastases(>20). Her KPS was graded at 70. Her cognitive function was assessed, according to the Mini-Mental State Examination (score of 22) and Montreal Cognitive Assessment (MoCA) on whichshe scored 19.

FIGURE 3: Demonstration of course of intracranial diseasewith serial magnetic resonance imaging (MRIs) (axial T1 withcontrast enhancement) from the targeted therapy to the lastfollow-up.Abbreviations on the left represent different stages of treatment: RS 1-5 – MRIs duringradiosurgeries, TT – MRI before the initiation of targeted therapy, TTresponse – MRIdemonstrating maximum response to targeted therapy, WBRT – MRI before the whole brainradiotherapy, Last FU – the last MRI.

The color of the contour indicates the stage when the lesion was treated: yellow – the 1stradiosurgery, orange – the 2nd radiosurgery, pink – the 3rd radiosurgery and hypofractionation,red – the 4th radiosurgery, blue – lesions before the initiation of targeted therapy, green –lesions removed with surgical intervention, purple – the 5th radiosurgery.

Arrows point on posttreatment changes after the 3rd irradiation in the area of septa pellucida;asterisk indicates the hemorrhage which emerged in one of the lesion treated with the 4thradiosurgery.

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In February 2017, the whole brain radiotherapy was performed with 10 fractions of 3 Gy (Figure3). The irradiation was performed along with targeted therapy and dexamethasone (4 mg daily).The irradiation was combined with targeted therapy in an attempt to increase the treatmenteffectiveness with respect to severe progression. No skin toxicity was noted. The MRI in onemonth demonstrated cystic transformation and enlargement of two lesions in the right frontallobe with mass effect, minor decrease of several lesions, and stabilization of others. No distinctnew metastases were detected.

In March 2017, the surgical resection of two lesions in the right frontal lobe was performed(Figure 3). After the intervention, epileptic seizures and left-sided hemiparesis (grade 2 musclestrength) developed. In April 2017, 17 growing lesions were treated with Gamma-Kniferadiosurgery up to marginal dose of 18 Gy prescribed to 53-89% isodose line (Figure 3). Themean target volume was 0.891 ccm (0.182-5.292 ccm). In two months after radiosurgery, MRIrevealed regression of postsurgical changes, minor enlargement of several non-irradiatedlesions (Figure 3). The irradiated lesions were stable. No new lesion emerged.

The patient died in three months after the last radiosurgery (49 months after the firstradiosurgery), due to intracranial and extracranial progression. The disease course isdemonstrated in Figure 4.

FIGURE 4: The disease course.Abbreviations for treatments are the following: RS 1-5 – radiosurgeries, H – hypofractionatedirradiation, ChT – chemotherapy, TT – targeted therapy, WBRT – whole brain radiotherapy, S –surgery.

DiscussionWe have presented a case of a patient with multiple melanoma brain metastases. The case can

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be interesting for specialists because of the patient’s lifetime which was much longer thancould be expected, and abscopal effect noticed.

It is known that the progression of the melanoma can often emerge with a significant time gapafter the treatment of a primary cutaneous lesion. Regional lymph nodes metastases develop ina median of 16–19 months, and direct distant metastases occur in a median of 24–25 months[1]. The same was seen in the case discussed. The regional metastases appeared in 12 monthsafter excision of the cutaneous lesion, and the brain metastases occurred in 25 months. Afterthe development of distant metastases, the disease course becomes more vigorous thatsignificantly affects lifetime expectation [3].

According to graded prognostic assessment (GPA) index, the estimated median survival timefor the patient should be 8.3 months (age < 70 years, KPS 90-100, extracranial metastases arepresented, brain metastases > 4, BRAF positive) with the interval of 3.9-18.2 months for 25th-75th percentile range. The patient presented survived for 49 months after detection of brainmetastases. Due to organizational problems, the patient did not receive systemic treatment fora long time. Chemotherapy with Cisplatin and Temozolomide was started in 12 months afterthe first radiosurgery. Although, according to published data, this treatment, as well as otherchemotherapy regimens, is characterized by low response rates and short progression-freesurvival in patients with metastatic melanoma [4]. The targeted therapy with Dabrafenib andTrametinib was launched only in 30 months after the first radiosurgery, and the patientsurvived for 19 months after its onset.

It is difficult to establish, what was the reason for such prolonged survival – the treatmentitself, tumor properties or both.

Melanoma is considered to be radioresistant tumor [6]. That is the reason for low effectivenessof whole brain irradiation [5]. Higher doses delivered with radiosurgery appear to be moreeffective. Radiosurgery provides pretty good local control about 49-97% [4]. The median overallsurvival in patients with brain metastases treated with radiosurgery is 5.3-10.4 months [4].Multiple radiosurgeries are associated with better survival [7]. Solitary lesion oroligometastases are associated with better survival than multiple lesions [4]. In our observation,radiosurgery provided rather high local growth control, and the rate of emergence of new brainmetastases enabled to perform repeated irradiations. Although large studies are needed toidentify if the multiple radiosurgeries lead to extended survival or prolonged survival allowsto perform multiple radiosurgeries.

The second reason for good survival of the patient could be the abscopal effect observed. It wasmanifested by the complete regression of intradermal metastases after the second radiosurgeryof brain lesions without any systemic treatment. The abscopal effect is defined as a regressionof metastases situated at a distance from the irradiated tumor of the same origin. More oftenthe abscopal effect was detected in patients who had received both irradiation and immunetherapy (Ipilimumab in most published cases) [6]. The patients with abscopal effectdemonstrated significantly higher survival comparing the patients without such event [6].There are only few cases described where irradiation only induced this effect in melanomapatients [6]. The similar mechanism may lead to vitiligo emergence after radiotherapy formelanoma [8]. There are also cases described where surgical intervention induced reduction ofdistant melanoma metastases [9]. Discussing the abscopal effect, we should mention theopportunity of spontaneous regression of the primary melanoma and/or metastases. Kalialis, etal. presented the review of 76 cases of spontaneous regression of melanoma metastases [10].The spontaneous regression was much more common in primary melanoma than in metastases.The authors identified factors (operative trauma, infection, immunologic factors, etc.) whichcould have stimulated the immune response in the main part of cases. So, it seems that the

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significant part of spontaneous regressions is presented by some kind of abscopal effect.

The launch of targeted therapy also seems to be an important factor affecting survival. In thecase, it was started in 30 months after the first radiosurgery and was administered during 19months until the patient’s death. The implementation of this treatment has influencedthe prognosis of the patients with melanoma dramatically. Compared to standardchemotherapy, both BRAF- and MEK-inhibitors separately significantly improve the survival ofpatients with metastatic melanoma, and the combination of both appears to be even moreeffective [3, 5].

ConclusionsIn the case, we have presented a rare case of the patient with melanoma brain metastaseswhich stands out due to significantly long survival period. The patient died in 49 months afterthe first radiosurgery for multiple brain metastases, whilst the median survival time had beenestimated as only 8.3 months, according to GPA index. The prolonged survival in the case canbe connected with multiple irradiations (five courses of radiosurgery, whole brainradiotherapy, and stereotactic hypofractionation), the abscopal effect emerged (clearlymanifested by regression of intradermal lesions after the second radiosurgery), and conductionof targeted therapy (launched 30 months after the first radiosurgery and lasted for 19 months).So, consistent timely application of different stereotactic irradiation techniques and targetedtherapy can lead to “chronization” of the disease, and, thus, improve the survival even in suchunfavorable diagnosis as melanoma with multiple brain metastases.

Additional InformationDisclosuresHuman subjects: Consent was obtained by all participants in this study. Conflicts of interest:In compliance with the ICMJE uniform disclosure form, all authors declare the following:Payment/services info: All authors have declared that no financial support was received fromany organization for the submitted work. Financial relationships: All authors have declaredthat they have no financial relationships at present or within the previous three years with anyorganizations that might have an interest in the submitted work. Other relationships: Allauthors have declared that there are no other relationships or activities that could appear tohave influenced the submitted work.

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